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Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
Seminar 09-04-2014 Osteoporose en cni
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Seminar 09-04-2014 Osteoporose en cni

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  • 1.    Osteoporosebehandeling  bij  CKD         Joop  van  den  Bergh,  internist-­‐endocrinoloog   VieCuri  MC  Noord-­‐Limburg   Maastricht  UMC+   UHasselt,  België  
  • 2. CBO  guideline  2011     Osteoporose  en  fractuurprevenIe   1.  PaIents  at  increased  risk  for  fracture     2.  EvaluaIon  of  skeletal  status  (DEXA/VFA)   3.  AnI-­‐osteoporosis  therapy:   •  BMD  T-­‐score  ≤  -­‐2.5   •  Vertebral  fracture(s)  
  • 3. Studies  of  fracture  risk  associated  with  CKD   Kidney  InternaIonal  2008:  721–731   •  High  risk  of  fracture  because  of  low  bone  mineral  density   •  Resembles  or  is  higher  than  in  postmenopausal  osteoporosis    
  • 4. However     •  The  mineral  and  bone  disorder  associated  with  CKD   (CKD–MBD)  is  more  complex  than  osteoporosis  and   the  same  treatments  might  not  be  appropriate.    
  • 5.    Renal  osteodystrophy:  a  complex  interplay  of  geneIc,  growth   and  cellular  factors,  some  of  which  inhibit  bone  formaIon,   whereas  others  sImulate  bone  resorpIon    
  • 6. Prevalence  of  low,  normal,  and  high  bone  turnover  in   black  and  white  CKD  paIents  on  maintenance  dialysis   JBMR  2011:  1368–1376   Review  of  630  bone  biopsies    
  • 7. JBMR  2011:  1368–1376  
  • 8. EvaluaIons  and  limitaIons  in  clinical  pracIce   •  Laboratory  parameters   •  Bone  turnover  markers   •  BMD  /  DEXA   •  HRpQCT   •  Bone  biopsy  
  • 9. Laboratory  parameters  
  • 10. Bone  turnover  markers:   levels  dependent  on  eGFR   Moorthi  et  al.  Kidney  InternaIonal  2013:886–894  
  • 11. Studies  of  imaging  modaliIes  to  assess  fracture  status  in  paIents   with  CKD  that  report  test  diagnosIc  characterisIcs   Kidney  InternaIonal  2008:  721–731  
  • 12. HR-­‐pQCT=  High  resoluIon  periferal  quanItaIve  computer  tomography  
  • 13. HR-­‐pQCT  radius  (lei)  and  Ibia  (right)     B  healthy,  post-­‐  menopausal     C  predialysis  with  CKD  and  without  fracture   D  predialysis  with  CKD  with  prevalent  fracture   J  Am  Soc  Nephrol  21:  1371–1380,  2010  
  • 14. BMD  and  HR-­‐pQCT  vs  fracture  predicIon   •  while  both  tests  were  able  to  discriminate  fracture  status,  the  addiIon  of   HR  pQCT  measures  to  BMD  by  DXA  did  not  improve  fracture   discriminaIon  ability   Osteoporos  Int  2012:2805–2813  
  • 15. LimitaIons  in  clinical  pracIce   •  Overlap  in  laboratory  parameters   •  Bone  turnover  markers  influenced  by  eGFR   •  BMD  /  DEXA  provides  ‘only’  2D  density  parameters   •  PotenIal  role  of  HRpQCT  needs  to  be  further  studied   •  LimitaIons  for  bone  biopsies  (as  gold  standard)  in   clinical  pracIce   •  UlImately:  combinaIon  of  mulIple  imaging   techniques  and  biomarkers  that  are  specific  to  each   gender  and  race  in  CKD  to  predict  fracture  risk  
  • 16. Considered  together   •  Fracture  risk  appears  to  be  higher  than  in  age-­‐  and   BMD-­‐matched  paIents  without  CKD   •  In  predialysis  CKD  without  substanIal  derangements   in  markers  of  mineral  metabolism  BMD  by  DXA  can   be  used  to  diagnose  osteoporosis   Jamal  et  al.  Curr  Rheumatol  Rep  (2012)  14:217–223  
  • 17. CBO  guideline  2011     Osteoporose  en  fractuurprevenIe   1.  PaIents  at  increased  risk  for  fracture     2.  EvaluaIon  of  skeletal  status  (DEXA/VFA)   3.  AnI-­‐osteoporosis  therapy:   •  BMD  T-­‐score  ≤  -­‐2.5   •  Vertebral  fracture(s)  
  • 18. Therapy  should  depend  on  the  underlying   pathophysiology    
  • 19. Resorption Formation Teriparatide/ rec PTHBisphosphonates SERMs Denosumab % Change vs. baseline Bone  turnover  and  anI-­‐osteoporosis  medicaIon   Strontium Ranelate
  • 20.  Nat.  Rev.  Nephrol.  Online  October  2013     Bone  Biopsies  with  tetracycline  double  labelling    
  • 21.  J  Bone  Miner  Res  1997;12:191–199   Bone  Biopsies  with  tetracycline  double  labelling      Nat.  Rev.  Nephrol.  Online  October  2013    
  • 22. Normal  bone  turnover   hop://courses.washington.edu/bonephys  
  • 23. Adynamic  bone   hop://courses.washington.edu/bonephys  
  • 24. OsteiIs  fibrosa  cysIca   hop://courses.washington.edu/bonephys  
  • 25.  J  Bone  Miner  Res  1997;12:191–199   Bone  Biopsies  with  tetracycline  double  labelling      Nat.  Rev.  Nephrol.  Online  October  2013    
  • 26. Fracture  outcomes  in  paIents  with  CKD–MBD   •  No  clinical  studies  to  assess  fracture  outcomes  in   paIents  with  CKD–MBD    
  • 27. Risedronate  in  PaIents  With  Age-­‐Related   Reduced  Renal    FuncIon  :    A  Pooled    Analysis    of  Nine  Clinical  Trials   n=301  vs  271   J  Bone  Miner  Res  2005;20:2105–2115.   new  vertebral  fractures  
  • 28. Bisphosphonate  use  in  paIents  with  CKD     •  Mainly  confined  to  those  with  early  stages  of  the  disease   •  Post  hoc  analyses  from  osteoporosis  clinical  trials:   –  paIents  with  mild  CKD  (but  normal  Ca,  AF  and  PTH)  have  a  similar   reducIon  in  fractures  to  that  observed  in  paIents  without  CKD   •  Histological  findings:  in  only  one  single-­‐centre,  observaIonal  study   –  in  all  13  paIents  with  CKD  stage  2–4  who  had  taken  bisphosphonates,   bone  biopsies  revealed  adynamic  bone  disease*.   •  The  KDIGO  commioee  could  not  idenIfy  any  clinical  trial  that  met   their  minimum  criteria  for  incorporaIon  into  their  consensus   guidelines:  inclusion  of  at  least  50  paIents  and  a  duraIon  of  at   least  6  months.   *Blood  Purif.  2010:293-­‐99  
  • 29. jnephrol  2013;  26  (3):  450-­‐455   35%  administered  dose  cleared  by  hemodialysis  
  • 30. Acute  Kidney  Injury  and  Bisphosphonate  Use   •  Preclinical  and  clinical  observaIons  reveal  that  all  BPs  can   potenIally  cause  acute  tubular  necrosis   •  Decline  in  GFR,  coupled  with  decreased  renal  blood  flow,   leads  to  reduced  drug  clearance  and  increased  concentraIon   of  drugs  in  the  renal  medulla   •  Mainly  aier  iv  dosing   •  In  cancer  paIents  (high  dose  and  co-­‐morbidity)   J  Oncology  PracIce  2013:101-­‐106  
  • 31. Raloxifene  (SERM)   •  Raloxifene  is  excreted  via  hepaIc  metabolism,  and  serum   drug  concentraIons  are  about  1.4  Imes  higher  in  paIents   with  CKD  than  in  individuals  with  normal  renal  funcIon   •  Aier  1  year  raloxifene,  lumbar  spine  BMD  (trabecular  bone)   significantly  improved,  femoral  neck  BMD  (corIcal  bone)  did   not  change  significantly   •  Incidence  of  breast  cancer  is  lowered  by  70%   •  However,  raloxifene,  like  oestrogen,  increases  the  risk  of   thromboembolism   Kidney  InternaIonal  2003:2269–2274  
  • 32. Denosumab   •  MAB  that  targets  the  osteoclast-­‐differenIaIon   cytokine  RANKL   –  Reducing  the  number  of  osteoclasts  and  bone  formaIon   rates     •  Is  not  excreted  by  the  kidney  
  • 33. JBMR  2012:  1471   GFR  at  baseline  by  Cockcroi-­‐Gault  esImaIon:   •  normal  renal  funcIon  (GFR  >80  mL/min/1.73m2)   •  mild  CKD  (GFR  50–80  mL/min/1.73m2)   •  moderate  CKD  (GFR  30–49  mL/min/1.73m2)   •  severe  CKD  (GFR  <30  mL/min/1.73m2)   •  kidney  failure  requiring  hemodialysis  
  • 34. Denosumab  in  paIents  with  CKD   •  None  had  stage  5  CKD   •  Fracture  risk  reducIon  and  changes  in  BMD  at  all  sites  were  in  favour  of  DMAb   •  The  test  for  treatment  by  subgroup  interacIon  was  not  staIsIcally  significant,   indicaIng  that  treatment  efficacy  did  not  differ  by  kidney  funcIon   JBMR  2011;1829  
  • 35. •  Denosumab  has  not  been  available  long  enough  to  assess  its   long-­‐term  safety  in  paIents  with  CKD–MBD   •  Problems  related  to  suppression  of  bone  formaIon  are  likely   to  be  seen     Denosumab  in  paIents  with  CKD  
  • 36. Hypocalcemia  aier  denosumab  in  severe  CKD   JBMR  2012:  1471   Calcium  and  vitamin  D  supplementaIon  was  not  iniIally  required  by   the  study  protocol,  but  was  added  during  the  trial   No  subject  who  received  adequate  calcium  and  vitamin  D   supplementaIon  became  hypocalcemic.  
  • 37. Hypocalcemia   •  Increased  risk  of  post-­‐denosumab  and  iv  bisphophonate  hypocalcaemia  in   renal  impairment  may  result  from  sudden  inhibiIon  of  the  high  bone   turnover  that  occurs  in  secondary  hyperparathyroidism   •  Is  preventable  with  adequate  calcium  and  vitamin  D  supplementaIon   •  Measurement  of  serum  calcium  levels  at  8–14  days  post-­‐denosumab  may   be  useful  to  allow  Imely  detecIon  of  hypocalcaemia  and  insItuIon  of   early  treatment   Intern  Med  J.  2013  Nov;43(11):1243-­‐6  
  • 38. Bone  turnover  and  BMD  aier  disconInuaIon  of  Denosumab     JCEM  2011:972–980  
  • 39. Am  J  Nephrol  2012;36:238–244   HD  paIents  
  • 40. HD  paIents   •  TeriparaIde  improved  BMD  with  adynamic  bone   disease,  although  no  staIsIcal  significance   •  PaIents  with  osteiIs  fibrosa,  ibandronate  did  not   improve  BMD  while  cinacalcet  reduced  BMD   Am  J  Nephrol  2012;36:238–244  
  • 41. Cinacalcet  Effect  on  Risk  of  Fractures   Cunningham J, et al. Kidney Int. 2005;68:1793-1800. Week Event-FreeProbability 0 4 8 12 16 20 24 28 32 36 40 44 48 52 0.75 0.95 1.00 n = 487Placebo n = 697Cinacalcet Placebo Cinacalcet 0.90 0.85 0.80 470 445 419 404 367 314 136 132 120 117 112 109383 656 614 574 554 485 392 132 131 125 115 110 106513 P = 0.04 Pooled analysis of safety data from 4 similarly designed randomized, double-blind, placebo- controlled trials All patients received standard care with phosphate binders and vitamin D, if prescribed.
  • 42. Risk  of  Hip  Fracture  May  be  Greater  Aier   Parathyroidectomy   1,0   1,7   0,0   0,2   0,4   0,6   0,8   1,0   1,2   1,4   1,6   1,8   2,0   No  Parathyroidectomy   Parathyroidectomy   Adjusted  Odds  Ra;o  for  Hip  Fracture   Jadoul  M,  et  al.  Kidney  Int.  2006;70:1358-­‐1366.   Dialysis  Outcomes  Prac;ce  PaBerns  Study  analysis  of  8,978  pa;ents  on          hemodialysis  with  and   without  a  history  of  parathyroidectomy  (2002-­‐2004)     P  =  0.02  
  • 43. TeriparaIde   •  Recombinant  PTH  (1-­‐34)     –  Anabolic  effect     •  Small  observaIonal  studies  suggest  that  teriparaIde  might  be   beneficial  in  paIents  with  CKD–MBD     –  who  have  adynamic  bone  disease   –  who  have  undergone  parathyroidectomy    
  • 44. Conclusions   •  PaIents  with  CKD   –  Have  a  high  risk  of  fracture  owing  to  their  low  BMD   –  ConvenIonal  medicaIons  for  osteoporosis  are  effecIve  at   reducing  fracture  rates  in  stage  3  CKD  and  normal  PTH,  Ca   and  phosphate  measurements   –  In  stage  4–5  CKD,  or  those  with  abnormal  PTH  and  mineral   values,  the  available  data  are  insufficient  to  determine   whether  these  commonly  used  medicaIons  are  effecIve   against  fractures  
  • 45. Conclusions   •  Alendronate,  risedronate   •  Zoledronate  (iv)   •  Denosumab       •  Raloxifene     •  TeriparaIde   •  Cinacalcet   •  Not  recommended  CrCl  <  30  (some  data   for  risedronate  if  CrCl  15-­‐30)   •  Contra-­‐indicated  CrCl  <  35   •  Might  be  useful  in  hypercalcemia   •  Risk  of  hypocalcemia  CrCl  <  30,  risky  for   low  bone  turnover,     •  No  concerns,  in  HD  beneficial  effects;   the  best  current  choice  in  women  with   CKD  without  VTE  problems   •  Benefit  in  low  PTH  en  low  BMD   •  Possible  effect  on  fractures  in  SHPT  

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